For example, articular cartilage is hyaline cartridge that is composed of a small number of cells, collagenous extracellular matrix, abundant proteoglycans and water. In the case of bone, since vascular and neural networks are present and bone has the ability to self-repair, even if a fracture has occurred, the fracture is frequently completely repaired. However, articular cartilage lacks vascular and neural networks. Consequently, it has virtually no potential for self-repair, and in the case of the formation of large cartilage defects in particular, the cartilage defect is not adequately repaired. Even at those portions that are repaired, fibrous cartilage is formed that has different mechanical properties than hyaline cartilage. Consequently, when a cartilage defect is formed, joint pain and loss of function are brought about that frequently progress to osteoarthritis. In addition, a cartilage defect can reach over a broad range as a result of symptoms progressing from the initial stages of osteoarthritis that began with wear of the surface of articular cartilage due to aging or excessive joint usage.
In this manner, since articular cartilage lacks an adequate self-repair ability, surgical procedures are required to treat cartilage injuries, examples of which include mosaicplasty, microfracture, drilling, abrasion and debridement. Among these, microfracture, drilling and abrasion are referred to as marrow stimulation techniques, and promote bleeding from bone marrow to induce bone marrow-derived cartilage precursor cells in anticipation of their differentiation into cartilage. However, these techniques have limitations with respect to cartilage defects covering a wide area, and cartilage regenerated by these methods is in the form of fibrous cartilage having different mechanical properties than hyaline cartilage.
Peterson et al. and Grande et al. tested an autologous chondrocyte implantation (ACI) technique in rabbit partial thickness articular cartilage in 1984. ACI is a technique involving the harvesting and culturing of tissue from a patient's own normal cartilage, implanting the cultured cells at an affected area while suspended in a medium, and covering the cartilage defect with the periosteum to prevent leakage of the cells. ACI was first applied clinically in 1994 and has currently been in practice for more than 15 years. Several successful outcomes have been reported. However, recent clinical studies have reported that ACI does not yield significantly superior results when compared with other techniques for repair of articular cartilage defects.
There are two major reasons for these unfavorable results obtained with ACI. The first is the technical difficulty associated with fixing the cells and scaffold to the cartilage defect and covering the defect with a periosteal flap. The ACI technique requires a wide arthrotomic exposure of the joint for suturing the periosteal flap to cover the cell suspension. Moreover, several complications associated with the periosteal flap have been reported, including periosteal hypertrophy, defect formation and intra-articular adhesion. The other reason involves limitations on the use of chondrocytes. Chondrocytes rapidly lose their differential phenotype in monolayer cultures, transforming into fibroblasts. Another problem is that although ACI requires cartilage to be harvested from a non-weight-bearing site of the joint, donor sites remain problematic since chondrocytes are harvested there from.
On the other hand, attempts are also progressing on the use of natural polymers such as collagen, chitosan, agarose and alginic acid in regenerative therapy of articular cartilage. In particular, alginic acid is a polysaccharide extracted from brown algae such as Ecklonia, Eisenia and Laminaria that has the property of crosslinking following the addition of calcium or other divalent metal ions, and attempts have been made to apply alginic acid to injured sites by utilizing this property to embed cells such as chondrocytes, growth factors and so on in a gel thereof (see, for example, References 1, 2, 3, 4 and 5).
For example, Reference 1 discloses an alginate gel comprising a mixture of a soluble alginate and an insoluble alginate/gel, while References 2, 3 and 4 disclose the use of alginate beads. In Reference 2, alginic acid can be used as a carrier that does not impart any disadvantageous effects on an injured site, although alginic acid itself is discussed as not having any therapeutic effects. In addition, Reference 4 discloses that chondrocytes embedded in alginate beads were not observed to fuse to host tissue after transplanting to a rabbit cartilage defect. In addition, although alginate beads are required to be applied by being pressed into a defect, since it is necessary to produce beads that match the size of the defect, their use in the actual clinical setting is technically difficult. Reference 5 discloses a graft in which chondrocytes are suspended in sodium alginate and injected into a rabbit cartilage defect followed by curing the surface with CaCl2 solution, wherein although normal cartilage tissue is formed, fibrous cartilage is formed in the case of applying only alginic acid to the cartilage defect without containing cells.
In addition, research is progressing on the use of collagen sponge and the like as a cell scaffold as an example of attempts to use mesenchymal stem cells for cartilage regenerative therapy. Although methods involving transplantation of mesenchymal stem cells following in vitro differentiation to chondrocytes, and methods involving transplantation of mesenchymal stem cells without differentiating have been considered, there is still continuing debate over which utilization method is optimal (Reference 6).
Since cartilage defects in osteoarthritis (OA) occur over a wide range and in regions subjected to loads, their repair by transplant or regenerative therapy is considered to be difficult. Those cartilage defects eligible for cartilage regeneration by cell transplant as described above are limited to partial cartilage defects caused mainly by sporting activities or trauma. Treatment of osteoarthritis focuses primarily on the removal of pain and inflammation at the affected area, and is commonly treated overseas with administration of non-steroid anti-inflammatory drugs. However, since renal function may be depressed in elderly patients, continuous oral administration of non-steroid anti-inflammatory drugs may be difficult from the viewpoint of safety. Products incorporating hyaluronic acid, which is a component of cartilage synovial fluid, improve the lubricating function of joints by being administered into a joint, and since these products also having analgesic action, they are widely used as joint function improving agents for osteoarthritis. However, since there is ultimately no other choice than to replace the joint with an artificial joint in severe cases of osteoarthritis in which joint damage has progressed, there is a desire for the development of a novel therapeutic drug.